Peripheral arterial disease (PAD) is a common chronic disease, affecting 8 million Americans, and is associated with increased risk of cardiovascular (CV) morbidity and mortality. Furthermore, intermittent claudication, critical leg ischemia, and amputation resulting from PAD adversely affect quality of life and functional status. Even asymptomatic PAD and is associated with functional status, functional decline and loss of mobility. An ankle brachial index (ABI) < 0.90 indicates PAD; however, by this time usually hemodynamically significant fixed stenotic lesions exist in lower extremity arteries. Measures such as femoral artery intima media thickness (IMT) and femoral artery compliance, as well as presence and characteristics of minimally obstructive femoral plaques may be more sensitive indicators of pre-clinical PAD, i.e. atherosclerosis and vascular dysfunction in the femoral artery that develops much earlier in the course of the disease than an abnormal ABI. More anatomically and physiologically proximal information regarding the vasculature can be obtained and the degree of atherosclerosis more precisely characterized with these femoral artery measures. Thus, we propose to use data from the San Diego Population Study (SDPS), an ethnically diverse prospective cohort of 1103 men and women with an average age of 70 years designed to study PAD and venous disease, to investigate femoral artery atherosclerosis measures and femoral artery compliance. Specifically, we propose to examine the association of femoral artery atherosclerosis and compliance with 1) measures of functional status, 2) exercise induced leg ischemia, and intermittent claudication, as well as 3) incident cardiovascular disease (CVD), and total and CVD mortality, and to determine whether endothelial dysfunction, hemostasis, coagulation play important roles in the physiological pathways as mediators. The current proposal involves reading femoral artery ultrasounds for atherosclerosis and compliance measures, and measuring circulating markers of endothelial dysfunction, hemostasis, and coagulation. As part of this proposal, participants will also be followed-up for incident events and mortality for at least 5 years. The SDPS has stored blood samples, and has excellent Duplex ultrasound images of the common and superficial femoral arteries and the bifurcation of these two arteries, as well as available data on a variety of important risk factors. The results of this research will have important implications. Detection of pre-clinical PAD is important in reducing total and CVD mortality and CVD events and can help in identifying who may be at risk for declining functional status. Results from this study could contribute to new recommendations for 1) screening for pre-clinical PAD, which could ultimately reduce costs by avoiding invasive treatments such as leg revascularization, 2) exercise as early as at detection of pre-clinical disease, which would hopefully prevent or delay progression, 3) treatment of those with pre- clinical PAD with statins, for example, to delay or prevent progression of pre-clinical disease to clinical PAD. PUBLIC HEALTH RELEVANCE: Peripheral arterial disease (PAD) is a common chronic disease, affecting 8 million Americans; however, by the time the ankle brachial index (ABI) is abnormal (<0.90) indicating PAD, significant stenosis is already present in the lower extremities. Thus, using data from 1103 participants in the San Diego Population Study (SDPS), we aim to examine the associations of a number of femoral artery atherosclerosis measures and femoral artery compliance, which may be more sensitive indicators of pre-clinical lower extremity arterial disease (or preclinical PAD) and indicators which are present before an abnormal ABI, with 1) functional status measures including the summary performance score and SF-36 physical component score , 2) exercise-induced leg ischemia, and intermittent claudication, as well as 3) incident cardiovascular disease (CVD) events, and total and CVD mortality, and to determine whether these associations are mediated endothelial dysfunction, hemostasis and coagulation. The results of this study will have important implications, and may allow for detection of preclinical PAD before it progresses to PAD and treat or intervene at this stage, as well as finding targeted and cost-effective public health interventions to prevent events and declining functional status.